[ CAS No. 915213-54-6 ]

Name: 915213-54-6|Ethyl 2-(4,4-difluorocyclohexyl)acetate|97%
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Quality Control of [ 915213-54-6 ]

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Product Details of [ 915213-54-6 ]

CAS No. :	915213-54-6	MDL No. :	MFCD18909256
Formula :	C₁₀H₁₆F₂O₂	Boiling Point :	222.9±10.0°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	206.23 g/mol	Pubchem ID :	59304597
Synonyms :

Calculated chemistry of of [ 915213-54-6 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.9
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.49
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.75 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.56
Log Po/w (XLOGP3) :	2.55
Log Po/w (WLOGP) :	3.61
Log Po/w (MLOGP) :	2.48
Log Po/w (SILICOS-IT) :	2.91
Consensus Log Po/w :	2.82

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.46
Solubility :	0.713 mg/ml ; 0.00346 mol/l
Class :	Soluble
Log S (Ali) :	-2.75
Solubility :	0.367 mg/ml ; 0.00178 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.76
Solubility :	0.362 mg/ml ; 0.00175 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.03

Safety of [ 915213-54-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 915213-54-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 915213-54-6 ]
Downstream synthetic route of [ 915213-54-6 ]

[ 915213-54-6 ] Synthesis Path-Upstream 1~4

1
[ 915213-54-6 ]
[ 915030-40-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #2: With hydrogenchloride In water	The compound 223e (3.2 g, 15.5 mmol) was dissolved in MeOH (5 ml) and treated with LiOH (559 mg, 23.3 mmol) overnight. The reaction mixture was acidified by 3 N HCl to pH 4 and extracted with CH₂Cl₂. The extract was dried over Na₂SO₄and concentrated to afford 223f as brown oil (3 g, 100percent).

Reference： [1] Patent: US2006/264489, 2006, A1, . Location in patent: Page/Page column 78
[2] Patent: US2013/183269, 2013, A1, . Location in patent: Paragraph 1216; 1217
[3] Patent: US2015/23913, 2015, A1, . Location in patent: Paragraph 1461-1462
[4] Patent: WO2015/5901, 2015, A1, . Location in patent: Page/Page column 517; 518
[5] Patent: WO2006/122200, 2006, A1, . Location in patent: Page/Page column 53

2
[ 58012-34-3 ]
[ 915213-54-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 3 h;	The compound 223d (4.6 g) was dissolved in CH₂Cl₂(10 ml) and treated with diethylaminosulfur trifluoride (DAST, 5 ml) at room temperature for 3 hours. The reaction mixture was poured into ice/water (30 ml) and extracted with CH₂Cl₂. The extract was washed with satd. aqueous NaHCO₃, brine, dried over Na₂SO₄and concentrated to afford 223e as brown oil (3.2 g, 62percent).
0.4 g	With ethanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane at 20℃; for 16 h;	To a solution ofethyl 2-(4-oxocyclohexyl)acetate(0.4 g) inDCM(5 mL) was addedDeoxo-Fluor®(0.881 mL) andEtOH(0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO₃and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na₂SO₄, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution ofethyl 2-(4,4-difluorocyclohexyl) acetateinTHF/MeOH(2 mL) was added 1NNaOH(1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated to yield2-(4,4-difluorocyclohexyl)acetic acidas ayellowsolid.¹H NMR (400 MHz, DMSO-d₆) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).

Reference： [1] Patent: US2006/264489, 2006, A1, . Location in patent: Page/Page column 78
[2] Patent: WO2010/103429, 2010, A1, . Location in patent: Page/Page column 34-35
[3] Patent: US2013/183269, 2013, A1, . Location in patent: Paragraph 1216; 1217
[4] Patent: US2015/23913, 2015, A1, . Location in patent: Paragraph 1461-1462
[5] Patent: WO2015/5901, 2015, A1, . Location in patent: Page/Page column 517; 518
[6] Patent: WO2006/122200, 2006, A1, . Location in patent: Page/Page column 52

3
[ 1283719-20-9 ]
[ 915213-54-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8321 - 8336

4
[ 22515-18-0 ]
[ 915213-54-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8321 - 8336

[ 915213-54-6 ] Synthesis Path-Downstream 1~24

1
[ 915213-54-6 ]
[ 915030-40-9 ]

Yield	Reaction Conditions	Operation in experiment
100%		The compound 223e (3.2 g, 15.5 mmol) was dissolved in MeOH (5 ml) and treated with LiOH (559 mg, 23.3 mmol) overnight. The reaction mixture was acidified by 3 N HCl to pH 4 and extracted with CH2Cl2. The extract was dried over Na2SO4 and concentrated to afford 223f as brown oil (3 g, 100%).
	With sodium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 16h;	Cap N-1: 2-(4,4-difluorocyclohexyl)acetic acid [1216] ethyl 2-(4-oxocyclohexyl)acetate (0.4 g) in DCM (5 mL) was added Deoxo-Fluor (0.881 mL) and EtOH (0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3 and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate in THF/ MeOH (2 mL) was added 1N NaOH (1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).
	With methanol; sodium hydroxide; In tetrahydrofuran; at 20℃; for 16h;	To a solution ofethyl 2-(4-oxocyclohexyl)acetate(0.4 g) inDCM(5 mL) was addedDeoxo-Fluor(0.881 mL) andEtOH(0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution ofethyl 2-(4,4-difluorocyclohexyl) acetateinTHF/MeOH(2 mL) was added 1NNaOH(1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield2-(4,4-difluorocyclohexyl)acetic acidas ayellowsolid.1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).

	With methanol; sodium hydroxide; In tetrahydrofuran; at 20℃; for 16h;	To a solution of ethyl 2-(4-oxocyclohexyl)acetate (0.4 g) in DCM (5 mL) was added Deoxo-Fluor (0.881 mL) and EtOH (0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. aHC03 and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2S04, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution of ethyl 2-(4,4-difluorocyclohexyl) acetate in THF/MeOH (2 mL) was added IN NaOH (1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with IN HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2S04, filtered and concentrated to yield 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid. 1H NMR (400 MHz, DMSO-i) ppm 12.13 (1 H, br. s.), 2.06 - 2.28 (3 H, m), 1.92 - 2.03 (1 H, m), 1.72 - 1.91 (4 H, m), 1.31 - 1.48 (1 H, m), 1.10 - 1.31 (2 H, m).
		KOH (2.1 g, 32 mmol) was added to a solution of (4,4-difluoro-cyclohexyl)-acetic acid ethyl ester (1.3 g, 6.3 mmol) in MeOH-H2O (4:1, 50 mL). The mixture was stirred_for 3h at room temperature, concentrated, diluted with H2O (20 mL), washed with ether (50 mL). The aqueous layer was acidified to pH =2 and extracted with ethyl acetate (3 x 500 mL) and the combined organic phases were dried (MgSO4) and evaporated to give the title compound.

Reference： [1]Patent: US2006/264489,2006,A1 .Location in patent: Page/Page column 78
[2]Patent: US2013/183269,2013,A1 .Location in patent: Paragraph 1216; 1217
[3]Patent: US2015/23913,2015,A1 .Location in patent: Paragraph 1461-1462
[4]Patent: WO2015/5901,2015,A1 .Location in patent: Page/Page column 517; 518
[5]Patent: WO2006/122200,2006,A1 .Location in patent: Page/Page column 53

2
[ 58012-34-3 ]
[ 915213-54-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 3h;	The compound 223d (4.6 g) was dissolved in CH2Cl2 (10 ml) and treated with diethylaminosulfur trifluoride (DAST, 5 ml) at room temperature for 3 hours. The reaction mixture was poured into ice/water (30 ml) and extracted with CH2Cl2. The extract was washed with satd. aqueous NaHCO3, brine, dried over Na2SO4 and concentrated to afford 223e as brown oil (3.2 g, 62percent).
		A mixture of [bis(2-methoxyethyl)amino]sulfur trifluoride (2.7 g) and boron trifluoride diethyl etherate (0.1 ml_) in toluene (15 ml_) at 0 0C was allowed to stand for 1.3 h with occasional stirring. A solution of (4-Oxo- cyclohexyl)-acetic acid ethyl ester (Preparation 7, 1.38 g) in toluene (10 ml_) was added. The reaction mixture was stirred at 50 0C for 1 day. The mixture was then cooled to 0 0C and the mixture was added to 50 ml_ of 5 N NaOH and 100 ml_ of Et2O/Heptane (1 :1 ) at 0 ° C. After stirring for 30 min, the phases were separated. The organic layer was washed with 100 ml_ of water, 1 N HCI, and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the desired product. 1H NMR (400 MHz, CDCI3) delta ppm 1.18 - 1.40 (m, 6H), 1.62 - 1.93 (m, 4H), 1.98 - 2.14 (m, 2H), 2.19 - 2.30 (m, 2H), 4.12 (q, J=7.03 Hz, 2 H).
	With ethanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 20℃; for 16h;	Cap N-1: 2-(4,4-difluorocyclohexyl)acetic acid To a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (0.4 g) in DCM (5 mL) was added Deoxo-Fluor® (0.881 mL) and EtOH (0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3 and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate in THF/MeOH (2 mL) was added 1N NaOH (1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).

0.4 g	With ethanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 20℃; for 16h;	To a solution of<strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong>(0.4 g) inDCM(5 mL) was addedDeoxo-Fluor®(0.881 mL) andEtOH(0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution ofethyl 2-(4,4-difluorocyclohexyl) acetateinTHF/MeOH(2 mL) was added 1NNaOH(1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield2-(4,4-difluorocyclohexyl)acetic acidas ayellowsolid.1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).
	With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In ethanol; dichloromethane; at 20℃; for 16h;	To a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (0.4 g) in DCM (5 mL) was added Deoxo-Fluor® (0.881 mL) and EtOH (0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. aHC03 and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2S04, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution of ethyl 2-(4,4-difluorocyclohexyl) acetate in THF/MeOH (2 mL) was added IN NaOH (1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with IN HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2S04, filtered and concentrated to yield 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid. 1H NMR (400 MHz, DMSO-i) ppm 12.13 (1 H, br. s.), 2.06 - 2.28 (3 H, m), 1.92 - 2.03 (1 H, m), 1.72 - 1.91 (4 H, m), 1.31 - 1.48 (1 H, m), 1.10 - 1.31 (2 H, m).
	With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 20℃; for 72h;	[B is(2-methoxyethyl)amino] sulfur trifluoride (Deoxofluor.(R)., 7.5 g, 34.8 mmol) was added to a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> [Alonso F., et. al. Tetrahedron, 1995, 57, 10259-10280] (2.0 g, 10.9 mmol) in dichloromethane (20 mL). The mixture was stirred for 3 days at room temperature and quenched with sat. NaHCO3 (20 mL) and extracted with ethyl acetate (3 x 100 mL) and the combined organic phases were dried (MgSO4) and evaporated. The residue was purified with flash chromatography to give the title compound.

Reference： [1]Patent: US2006/264489,2006,A1 .Location in patent: Page/Page column 78
[2]Patent: WO2010/103429,2010,A1 .Location in patent: Page/Page column 34-35
[3]Patent: US2013/183269,2013,A1 .Location in patent: Paragraph 1216; 1217
[4]Patent: US2015/23913,2015,A1 .Location in patent: Paragraph 1461-1462
[5]Patent: WO2015/5901,2015,A1 .Location in patent: Page/Page column 517; 518
[6]Patent: WO2006/122200,2006,A1 .Location in patent: Page/Page column 52

3
[ 915213-54-6 ]
[ 74-88-4 ]
ethyl 2-(4,4-difluorocyclohexyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		Intermediate 232A: Ethyl 2-(4,4-difluorocyclohexyl)propanoate To a solution of <strong>[915213-54-6]ethyl 2-(4,4-difluorocyclohexyl)acetate</strong> (0.500 g, 2.424 mmol) in THF (10 mL) was added LDA (2.424 mL, 4.85 mmol, 2M in THF) dropwise at -78 C. and the reaction mixture was stirred at the same temperature for 45 min. MeI (0.606 mL, 9.70 mmol) was then added at -78 C. and the reaction mixture was slowly warmed to RT and stirred for 12 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2*25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP column, eluting with 5% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 232A as a pale yellow liquid (0.27 g, 50%). 1H NMR (300 MHz, chloroform-d) delta ppm 4.22-4.08 (m, 1H), 2.32 (quin, J=7.1 Hz, 1H), 2.20-2.02 (m, 2H), 1.88-1.76 (m, 2H), 1.75-1.62 (m, 3H), 1.51-1.35 (m, 2H), 1.33-1.23 (m, 4H), 1.20-1.11 (m, 3H).

Reference： [1]Patent: US9273058,2016,B2 .Location in patent: Page/Page column 253; 254; 255

4
[ 915213-54-6 ]
ethyl 2-(4,4-difluorocyclohexyl)-2-methylpropanoate [ No CAS ]

Reference： [1]Patent: US9273058,2016,B2

5
[ 915213-54-6 ]
2-(4,4-difluorocyclohexyl)-2-methylpropanoic acid [ No CAS ]

Reference： [1]Patent: US9273058,2016,B2

6
[ 915213-54-6 ]
2-(3-chloro-4-fluorophenyl)-N⁵-(2-(4,4-difluorocyclohexyl)propan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide [ No CAS ]

Reference： [1]Patent: US9273058,2016,B2

7
[ 1283719-20-9 ]
[ 915213-54-6 ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8321 - 8336
[2]Journal of the American Chemical Society,2019,vol. 141,p. 12536 - 12540

8
[ 915213-54-6 ]
2-(4,4-difluorocyclohexyl)ethanol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8321 - 8336
[2]Journal of the American Chemical Society,2019,vol. 141,p. 12536 - 12540

9
[ 915213-54-6 ]
[ 959600-89-6 ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8321 - 8336
[2]Journal of the American Chemical Society,2019,vol. 141,p. 12536 - 12540

10
[ 915213-54-6 ]
(E)-tert-butyl 2-(2-(4,4-difluorocyclohexyl)ethylidene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]